Abstract
Simple SummaryIn the 1990s, fluorescent in situ hybridization approaches made it possible to analyze the early stages of gene amplification in mammalian cells. These studies established breakage-fusion-bridge cycles as a major mechanism of intrachromosomal gene amplification. They also revealed that the amplified DNA perturbed nuclear architecture and led to micronucleation, which suggested a mechanism for the shortening of amplified units. The “interphase breakage model” postulated that the tremendous genomic instability occurring at early stages of gene amplification resulted from the interweaving of an amplification mechanism (breakage-fusion-bridge cycles) and of a deletion mechanism (micronucleation and stitching of DNA fragments retained in the nucleus). This model is strikingly consistent with recent data and conclusions obtained from live-cell imaging and single cell genome sequencing. The comparison of both sets of data suggests new questions to explore.Understanding the mechanisms underlying cancer genome evolution has been a major goal for decades. A recent study combining live cell imaging and single-cell genome sequencing suggested that interwoven chromosome breakage-fusion-bridge cycles, micronucleation events and chromothripsis episodes drive cancer genome evolution. Here, I discuss the “interphase breakage model,” suggested from prior fluorescent in situ hybridization data that led to a similar conclusion. In this model, the rapid genome evolution observed at early stages of gene amplification was proposed to result from the interweaving of an amplification mechanism (breakage-fusion-bridge cycles) and of a deletion mechanism (micronucleation and stitching of DNA fragments retained in the nucleus).
Highlights
In a recent issue of Science, Umbreit et al used live-cell imaging with single cell whole genome sequencing (Look-Seq) to analyze the cascade of genome rearrangements following the formation of a chromosome bridge in human cells [1]
fluorescent in situ hybridization (FISH) studies and the more recent Look-Seq analyses have provided remarkably consistent data, leading to conclude that BFB cycles, micronucleation and multiple interphase DNA breaks are interwoven to drive the evolution of cancer genomes
While both sets of studies suggested that an amplified chromosome may give rise to a micronucleus, the proposed mechanisms for micronucleation appear to differ: in the interphase breakage model, micronucleation would result from a nuclear blebbing of the amplified DNA, whereas Umbreit et al proposed that a micronucleus might be formed around a lagging broken chromosome
Summary
In a recent issue of Science, Umbreit et al used live-cell imaging with single cell whole genome sequencing (Look-Seq) to analyze the cascade of genome rearrangements following the formation of a chromosome bridge in human cells [1]. FISH with a probe for the amplification “driver” gene length, suggesting that their amplification resulted from an uneven segregation of driver sequences (conferring drug resistance) first revealed that early amplified units, within HSRs or DMs, were during successive cell cycles, rather than local over-replication [6,8,9,12]. A better understanding of the mechanisms involved came from two-color FISH analyses, with one probe for AMPD2, the amplification “driver” gene, and one probe for a passively co-amplified (“passenger”) marker [4] These experiments showed that the early intrachromosomal amplified units were organized as Mb-long inverted repeats with one or several orders of symmetry, which were perfectly explained by the operation of breakage-fusion-bridge cycles between sister chromatids (Figure 2).
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